EP0980254B1 - Pharmaceutical antiviral composition comprising glycyrrhizic acid and at least one protein endowed with antiviral activity - Google Patents
Pharmaceutical antiviral composition comprising glycyrrhizic acid and at least one protein endowed with antiviral activity Download PDFInfo
- Publication number
- EP0980254B1 EP0980254B1 EP98925588A EP98925588A EP0980254B1 EP 0980254 B1 EP0980254 B1 EP 0980254B1 EP 98925588 A EP98925588 A EP 98925588A EP 98925588 A EP98925588 A EP 98925588A EP 0980254 B1 EP0980254 B1 EP 0980254B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- lysozyme
- glycyrrhizic acid
- lactoferrin
- antiviral
- protein
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to a pharmaceutical antiviral composition
- a pharmaceutical antiviral composition comprising glycyrrhizic acid and at least one protein endowed with antiviral activity.
- Herpes Simplex Virus type 1 causes facial and oropharyngeal lesions ("Manual of Clinical Microbiology", Murray, Baron, Pfaller, Tenover, Yolken, 6 th edition, pages 876-883, American Society for Microbiology, Washington D.C., 1993).
- aciclovir is therefore the most used drug in the treatment of mouth and lip lesions (rash from fever) but its topical use often causes burning and irritation of mucous membranes. Moreover, aciclovir is fairly efficient when administered during the first infection, but is not very effective in the case of recurring infections, thus being non-resolutive and not preventing re-infection by Herpes Simplex Virus type 1.
- oral treatment has the disadvantage of causing side effects such as nausea, diarrhoea, itching, headaches, renal inadequacies and nephrotoxicity.
- glycyrrhizic acid shows a certain antiviral activity. At antiviral doses, it largely inhibits the synthesis of viral glycoproteins and only at very high doses does it also inhibit the cell glycoproteins synthesis. In fact while the action of the glycyrrhizic acid on the synthesis of proteins, both in normal cells and infected cells, is practically irrelevant even at doses of 4 mM, the synthesis of glyco-proteins shows a substantial difference in normal and infected cells.
- glycyrrhizic acid causes a reduction in the incorporation of glucosamine-H 3 of more than 10% in infected cells and no inhibition in normal cells.
- An increased dose of glycyrrhizic acid up to 1 mM causes an 80%reduction of the virus, no inhibition of the synthesis of glyco-proteins in the control and a 20% reduction in the synthesis of glycoprotein in infected cells.
- the synthesis of glyco-proteins in the normal cells is also slightly altered, but the production of the virus is inhibited by 99% ("L'Igiene Moderna", Pompei R. and Marcialis M.A., 83 , 385-391, 1985).
- Table A shows the results of tests carried out treating cells infected by HSV1 with 8 mM glycyrrhizic acid.
- the infected cells have been kept in contact with the glycyrrhizic acid for 2 hours at 37°C.
- the experimental results given in the Table show that there is a strong decrease in infection at 12, 17 and 22 hours and that the cells retain their cellular integrity.
- the inhibition is of about 2 logarithms at 12 hours from the infection and 3 logarithms (99.9%) at 22 hours from infection ("Nature", Pompei R. et al., 281, No. 5733, 689-690, 1979).
- Viral production (PFU/ml) after the following hours Hours 12 17 22 Control 3x10 6 5.4 x 10 6 2.6 x 10 7 Glycyrrhizic acid 8mM 4.2 x 10 4 1.2 x 10 4 1.1 x 10 4
- HSV1 anti-herpetic
- lysozymes such as turkey lysosyme, human lysozyme, chicken lysozyme, denaturated (heat-inactivated) chicken lysozyme and chicken lysozyme digested with trypsin
- Lysozymes are, in fact, enzymes which are widely spread in nature and cooperate in the defense of the organism against some infecting agents by causing or cooperating to the cleavage (i.e. lysis) thereof ("Mol. Cell. Biochem.”, Jollès et al., 63 , 165-189, 1984; "Anticancer Res.”, Save et al., 9 , 583-592, 1989).
- composition characterized in that it comprises glycyrrhizic acid and at least one protein having antiviral activity.
- the protein is selected from the group comprising the lysozymes and the lactoferrins.
- lysozymes are turkey lysozyme, human lysozyme, chicken lysozyme, heat-inactivated chicken lysozyme and chicken lysozyme digested with trypsin.
- the lysozyme is a chicken lysozyme or a human lysozyme.
- lactoferrins are bovine and human lactoferrins.
- the pharmaceutical composition of this invention is useful in the treatment of topical viral infections.
- the virus is of a herpetic type. Even more preferably it is the Herpes Simplex Virus type 1 (HSV1).
- the pharmaceutical compositions of this invention are prepared in the form of suitable dosage forms,
- suitable dosage forms are creams, ointments and medicated plasters, for topical administration.
- the dosage forms may also contain other conventional ingredients, such as: preservatives, stabilisers, surfactants, buffers, salts to regulate osmotic pressure, emulsifiers, sweeteners, colouring agents, flavouring agents and the like.
- the amount of active ingredients in the pharmaceutical composition of this invention may vary within a wide range depending on known factors such as, for example, stage and severity of the infection, body weight of the patient, type of the dosage form, administration route, number of dosage forms administered per day and the efficacy of the active ingredients. However, the optimum amount will be determined readily and routinely by a person skilled in the art.
- the dosage forms of the pharmaceutical composition of this invention may be prepared according to techniques which are well known to the pharmaceutical chemist, and comprise mixing, granulation, compression, dissolution and the like.
- Monolayers of VERO cells were plated on 24 wells plates and infected with about 1 HSV1 viral infecting unit x 100 cells for one hour at room temperature. Then different amounts from 0 to 8 mg/ml of chicken, turkey and human lysozymes were added in a thermostat at 37°C and in the presence of CO 2 (5%).
- the concentration of infecting viral particles produced for each dilution of lysozyme was titrated after centrifugation. Titration was carried out by diluting the content of each well from 10 -1 to 10 -7 and putting it in contact with cell monolayers in a multiwell having 6 wells each for 1 hour at room temperature.
- the cells were covered with a layer of nutritive agar and, after 48 hours of incubation, they were coloured with neutral red, and the macroscopically visible viral plaques were counted. Thus the inhibition percentage obtained on the viral plaque by lysozyme compared with the control was established.
- Example 2 It was carried out as Example 1 except that different amounts of from 0 to 1 mg/ml of glycyrrhizic acid alone were added to the monolayers of VERO cells infected with HSV1.
- the experimental results are shown in Table 2.
- Glycyrrhizic acid - Inhibition (%) of viral plaques Doses (mg/ml) 0.2 0.4 0 6 0.8 1 Inhibition (%) 0 10 ⁇ 4 27 ⁇ 7 50 ⁇ 8 75 ⁇ 12
- Example 1 It was carried out as Example 1 except that 0.5 mg/ml of glycyrrhizic acid and different amounts of chicken lysozyme of from 0 to 1 mg/ml were added to the monolayers of VERO cells infected with HSV1
- the associations of glycyrrhizic acid and lysozymes are characterized by a marked synergic effect.
- the inhibition (%) expected for an association comprising 0.5 mg/ml of chicken lysozyme and 0.5 mg/ml of glycyrrhizic acid is of about 35-40%.
- the results shown in Table 3 prove that the inhibition (%) of this association is about 84%.
- the synergy is confirmed by the FIC index, which in the case in examination is 0.125.
- the FIC index fractioned inhibiting concentrations
- a FIC index ⁇ 0.5 means that there is a significant synergy between the two products.
- Example 1 It was carried out as Example 1 except that different amounts of bovine and human lactoferrin were added to the monolayers of VERO cells infected with HSV1.
- Table 4 shows that the lactoferrins are not very toxic and that their viral action is already very pronounced at levels significantly below toxic ones.
- Example 1 It was carried out as Example 1 except that 0.5 mg/ml of glycyrrhizic acid and different amounts from 0 to 1 mg/ml of human lactoferrin were added to the monolayers of VERO cells infected with HSV1.
- the synergy is confirmed by the FIC index, which is 0.06.
- Example 1 It was carried out as Example 1 except that 0.5 mg/ml of glycyrrhizic acid, 0.1 mg/ml of human lactoferrin and different amounts of from 0 to 1 mg/ml of chicken lysozyme were added to the monolayers of VERO cells infected with HSV1.
- the associations of glycyrrhizic acid, lactoferrin and lysozymes are characterized by a marked synergic effect.
- the expected inhibition (%) of an association comprising 0.1 mg/ml of lactoferrin, 0.5 mg/ml of glycyrrhizic acid and 0.5 mg/ml of lysozyme is about 65%.
- the results shown in Table 6 show that the inhibition (%) of this association is about 98%.
Abstract
Description
Viral production (PFU/ml) after the following hours | |||
Hours | 12 | 17 | 22 |
Control | 3x106 | 5.4 x 106 | 2.6 x 107 |
Glycyrrhizic acid 8mM | 4.2 x 104 | 1.2 x 104 | 1.1 x 104 |
- glycyrrhizic acid (as ammonium salt) supplied by FLUKA AG;
- Herpes Simplex Virus type 1 supplied by the NIH, Rockville, Maryland;
- chicken lysozyme supplied by SIGMA;
- lactoferrin supplied by SIGMA;
- VERO cell from kidney of African green monkey from ICN FLOW, Costa Mesa, CA;
- Eagle medium modified by Dulbecco (DMEM), added with calf foetal serum, inactivated for 30' at 56°C, supplied by ICN FLOW, Costa Mesa, CA.
Inhibition (%) of viral plaques with various lysozymes | |||||||
Doses (mg/ml) | 0 | 8 | 6 | 4 | 2 | 1 | 0.5 |
Chicken | 0 | 93±3 | 82±4 | 71±6 | 60±6 | 49±5 | 20±4 |
Turkey | 0 | 89±5 | 80±4 | 68±5 | 55±6 | 45±5 | 10±3 |
Human | 0 | 90±5 | 79±6 | 70±4 | 59±4 | 45±3 | 18±3 |
Glycyrrhizic acid - Inhibition (%) of viral plaques | |||||
Doses (mg/ml) | 0.2 | 0.4 | 0 6 | 0.8 | 1 |
Inhibition (%) | 0 | 10±4 | 27±7 | 50±8 | 75±12 |
Inhibition (%) of viral plaques (Glycyrrhizic acid 0.5 mg/ml + Different doses of chicken lysozyme) | |||||
Chicken lysozyme/ doses (mg/ml) | 0.2 | 0.4 | 0.6 | 0.8 | 1 |
Inhibition (%) | 72±6 | 83±8 | 85±8 | 87±9 | 88±8 |
Inhibition (%) of viral plaques (Glycyrrhizic acid 0.5 mg/ml + Different doses of human lactoferrin) | |||||||||
H. lactoferrin doses mg/ml | 0 | 0.0075 | 0.015 | 0.031 | 0.062 | 0.125 | 0.250 | 0.5 | 1 |
Inhibition (%) | 30±2 | 30±4 | 50±6 | 50±5 | 60±10 | 80±15 | 100 | 100 | 100 |
Inhibition (%) of viral plaques (Glycyrrhizic acid 0.5 mg/ml and human lactoferrin 0.1 mg/ml + Different doses of chicken lysozyme) | |||||
Chicken lysozyme/ doses (mg/ml) | 0 | 0.25 | 0.5 | 0.75 | 1 |
Inhibition (%) | 48±2 | 95±5 | 98±2 | 99±1 | 100 |
Claims (4)
- A pharmaceutical composition characterized in that it comprises glycyrrhizic acid and at least one protein having antiviral activity provided, however, that when said protein is a lysozyme and the composition is in form of an aqueous solution it does not contain a salt of an alkali or alkaline-earth metal.
- A composition according to claim 1, characterized in that said protein is a lysozyme and/or a lactoferrin.
- A composition according to claim 2, characterized in that the lysozyme is selected from the group comprising chicken lysozyme, turkey lysozyme, human lysozyme, heat-inactivated chicken lysozyme, chicken lysozyme digested with trypsin.
- A composition according to claim 2, characterized in that lactoferrin is a human or bovine lactoferrin.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SI9830118T SI0980254T1 (en) | 1997-05-14 | 1998-05-06 | Pharmaceutical antiviral composition comprising glycyrrhizic acid and at least one protein endowed with antiviral activity |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT97MI001119A IT1291366B1 (en) | 1997-05-14 | 1997-05-14 | ANTIVIRAL PHARMACEUTICAL COMPOSITION INCLUDING GLYCYRHIZIC ACID AND AT LEAST ONE PROTEIN WITH ANTIVIRAL ACTIVITY |
ITMI971119 | 1997-05-14 | ||
PCT/EP1998/002797 WO1998051334A1 (en) | 1997-05-14 | 1998-05-06 | Pharmaceutical antiviral composition comprising glycyrrhizic acid and at least one protein endowed with antiviral activity |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0980254A1 EP0980254A1 (en) | 2000-02-23 |
EP0980254B1 true EP0980254B1 (en) | 2002-01-23 |
Family
ID=11377123
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98925588A Expired - Lifetime EP0980254B1 (en) | 1997-05-14 | 1998-05-06 | Pharmaceutical antiviral composition comprising glycyrrhizic acid and at least one protein endowed with antiviral activity |
Country Status (27)
Country | Link |
---|---|
US (1) | US6329339B1 (en) |
EP (1) | EP0980254B1 (en) |
JP (2) | JP2001525814A (en) |
KR (1) | KR100592193B1 (en) |
CN (1) | CN1114447C (en) |
AR (1) | AR012849A1 (en) |
AT (1) | ATE212232T1 (en) |
AU (1) | AU740944B2 (en) |
BG (1) | BG64748B1 (en) |
CA (1) | CA2289550A1 (en) |
CZ (1) | CZ291932B6 (en) |
DE (1) | DE69803565T2 (en) |
DK (1) | DK0980254T3 (en) |
EA (1) | EA003126B1 (en) |
ES (1) | ES2170501T3 (en) |
GE (1) | GEP20022672B (en) |
HK (1) | HK1028347A1 (en) |
HU (1) | HU224956B1 (en) |
IL (2) | IL132651A0 (en) |
IT (1) | IT1291366B1 (en) |
PL (1) | PL189218B1 (en) |
PT (1) | PT980254E (en) |
SK (1) | SK283584B6 (en) |
TR (1) | TR199902730T2 (en) |
UA (1) | UA63955C2 (en) |
WO (1) | WO1998051334A1 (en) |
ZA (1) | ZA983917B (en) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6303321B1 (en) | 1999-02-11 | 2001-10-16 | North Shore-Long Island Jewish Research Institute | Methods for diagnosing sepsis |
US7151082B2 (en) * | 1999-02-11 | 2006-12-19 | The Feinstein Institute For Medical Research | Antagonists of HMG1 for treating inflammatory conditions |
US7304034B2 (en) | 2001-05-15 | 2007-12-04 | The Feinstein Institute For Medical Research | Use of HMGB fragments as anti-inflammatory agents |
AU2003225073A1 (en) * | 2002-04-18 | 2003-11-03 | The University Of Iowa Research Foundation | Methods of inhibiting and treating bacterial biofilms by metal chelators |
US7696169B2 (en) * | 2003-06-06 | 2010-04-13 | The Feinstein Institute For Medical Research | Inhibitors of the interaction between HMGB polypeptides and toll-like receptor 2 as anti-inflammatory agents |
US7288250B2 (en) * | 2003-09-11 | 2007-10-30 | Critical Therapeutics, Inc. | Monoclonal antibodies against HMGB1 |
US20100040608A1 (en) * | 2005-07-18 | 2010-02-18 | Marie Wahren-Herlenius | Use of HMGB1 antagonists for the treatment of inflammatory skin conditions |
AU2006330807A1 (en) * | 2005-11-28 | 2007-07-05 | Medimmune, Llc | Antagonists of HMBG1 and/or rage and methods of use thereof |
IT1391170B1 (en) * | 2008-08-07 | 2011-11-18 | D M G Italia S R L | INTRA-NASAL TOPIC COMPOSITION USABLE IN CASE OF NASAL OBSTRUCTION |
US9416151B2 (en) | 2010-08-25 | 2016-08-16 | Lurong ZHANG | Use of glycyrrhetinic acid, glycyrrhizic acid and related compounds for prevention and/or treatment of pulmonary fibrosis |
WO2012026928A1 (en) * | 2010-08-25 | 2012-03-01 | Diacarta Llc | Use of glycyrrhetinic acid, glycyrrhizic acid and related compounds for prevention and/or treatment of pulmonary fibrosis |
CN106029089B (en) | 2014-02-21 | 2020-12-29 | 丘比株式会社 | Norovirus inactivator and method for producing same |
SG11201806868TA (en) | 2016-02-25 | 2018-09-27 | Applied Biological Laboratories Inc | Compositions and methods for protecting against airborne pathogens and irritants |
CN109022351B (en) * | 2018-09-28 | 2021-10-19 | 广州奇龙生物科技有限公司 | New application of recombinant human lysozyme |
EP4144363A1 (en) * | 2020-04-27 | 2023-03-08 | Guangzhou Century Clinical Research Co., Ltd | Drug, food and application of anti-coronavirus infection |
CN112135625B (en) * | 2020-04-27 | 2021-07-06 | 广州新创忆药物临床研究有限公司 | Medicine for preventing or treating COVID-19 new coronary pneumonia and application thereof |
CN113304253A (en) * | 2020-04-27 | 2021-08-27 | 湘北威尔曼制药股份有限公司 | Food for auxiliary prevention or auxiliary treatment of new coronary pneumonia and application thereof |
MX2021005280A (en) | 2021-05-04 | 2022-02-23 | Spv Timser S A P I De C V | Pharmaceutical composition containing pentacyclic triterpenoids. |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH085800B2 (en) * | 1986-12-19 | 1996-01-24 | エーザイ株式会社 | Aqueous formulation containing lysozyme chloride and dipotassium glycyrrhizinate |
JP2838720B2 (en) * | 1989-10-31 | 1998-12-16 | ゼリア新薬工業株式会社 | Stable eye drops |
JP4056099B2 (en) * | 1996-05-09 | 2008-03-05 | 森永乳業株式会社 | Preventive and therapeutic agents for parasitic diseases in aquatic animals |
-
1997
- 1997-05-14 IT IT97MI001119A patent/IT1291366B1/en active IP Right Grant
-
1998
- 1998-05-06 PL PL98336802A patent/PL189218B1/en not_active IP Right Cessation
- 1998-05-06 PT PT98925588T patent/PT980254E/en unknown
- 1998-05-06 CA CA002289550A patent/CA2289550A1/en not_active Abandoned
- 1998-05-06 AT AT98925588T patent/ATE212232T1/en not_active IP Right Cessation
- 1998-05-06 EA EA199901024A patent/EA003126B1/en not_active IP Right Cessation
- 1998-05-06 DE DE69803565T patent/DE69803565T2/en not_active Expired - Fee Related
- 1998-05-06 GE GEAP19985126A patent/GEP20022672B/en unknown
- 1998-05-06 DK DK98925588T patent/DK0980254T3/en active
- 1998-05-06 EP EP98925588A patent/EP0980254B1/en not_active Expired - Lifetime
- 1998-05-06 ES ES98925588T patent/ES2170501T3/en not_active Expired - Lifetime
- 1998-05-06 KR KR1019997010372A patent/KR100592193B1/en not_active IP Right Cessation
- 1998-05-06 AU AU77646/98A patent/AU740944B2/en not_active Ceased
- 1998-05-06 CN CN98805037A patent/CN1114447C/en not_active Expired - Fee Related
- 1998-05-06 SK SK1544-99A patent/SK283584B6/en not_active IP Right Cessation
- 1998-05-06 HU HU0002985A patent/HU224956B1/en not_active IP Right Cessation
- 1998-05-06 IL IL13265198A patent/IL132651A0/en active IP Right Grant
- 1998-05-06 TR TR1999/02730T patent/TR199902730T2/en unknown
- 1998-05-06 CZ CZ19993991A patent/CZ291932B6/en not_active IP Right Cessation
- 1998-05-06 WO PCT/EP1998/002797 patent/WO1998051334A1/en not_active Application Discontinuation
- 1998-05-06 US US09/423,611 patent/US6329339B1/en not_active Expired - Fee Related
- 1998-05-06 JP JP54879998A patent/JP2001525814A/en not_active Ceased
- 1998-05-08 ZA ZA983917A patent/ZA983917B/en unknown
- 1998-05-13 AR ARP980102218A patent/AR012849A1/en active IP Right Grant
- 1998-06-05 UA UA99126790A patent/UA63955C2/en unknown
-
1999
- 1999-10-29 IL IL132651A patent/IL132651A/en not_active IP Right Cessation
- 1999-12-08 BG BG103968A patent/BG64748B1/en unknown
-
2000
- 2000-12-07 HK HK00107849A patent/HK1028347A1/en not_active IP Right Cessation
-
2008
- 2008-12-25 JP JP2008331229A patent/JP2009102370A/en not_active Ceased
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